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Decades of discovery lead to unique drug trials for inherited intellectual disability

When the NICHD was founded in 1962, many children and adults with intellectual disabilities were cared for in overcrowded, understaffed institutions that isolated them from their families and communities. During this time it was broadly believed that the intellectual and functional capacities of individuals with intellectual disabilities either deteriorated, or at best remained stable over time. Many of the causes of intellectual disability were unknown, and little research was done to better understand or treat these conditions. Intellectual disability was accepted as permanent and irreversible.

Over time an increasing number of scientists became interested in studying intellectual disabilities and began to conduct research that focused on this population. Metabolic and genetic causes of intellectual disability were slowly becoming uncovered, and it was demonstrated that behavioral and educational interventions could have an impact on establishing new functional skills in these individuals. In parallel, community support services for both the individual and their families were established providing individuals with the opportunity to grow and learn. Intellectual disability was still viewed by many as permanent and irreversible; however, inroads were being made.

Today, that assumption is being further challenged. For the most common inherited form of intellectual disability, scientists now understand not only the genetic cause of the condition, but also how that specific gene affects the brain and body. With new advances in science, it has now become feasible to develop drugs that directly target the cause of symptoms related to specific intellectual disabilities.

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Fragile X Syndrome

Fragile X syndrome (FXS) is the most common inherited form of intellectual and developmental disability. Fragile X mainly causes intellectual disability, and patients often have IQs of 75 or less. Common behavior problems include hyperactivity and autistic-like features, including problems with sensation and emotions. Approximately one in 4,000 males and one in 8,000 females have full FXS.

There is currently no cure for FXS. However, the severity of symptoms can be reduced with medications used for attention deficit, hyperactivity, and anxiety. In addition, functional outcomes in individuals with FXS can be improved with supportive management, including speech therapy, occupational therapy, and educational and behavioral interventions.

The progression of Fragile X research and discoveries leading to the development and testing of potential treatments spans nearly 100 years. In 1991, NICHD-supported researcher Steve Warren and his colleagues were among the first scientists to identify the gene responsible for the fragile site as the FMR1 gene—the Fragile X Mental Retardation 1 gene.


Variability in Fragile X

Fragile X syndrome is caused by an expansion of a stretch of DNA (known as a CGG trinucleotide repeat) affecting the Fragile X Mental Retardation 1 (FMR1) gene on the X chromosome. Multiple copies of the CGG trinucleotide repeat results in a failure to make the Fragile X mental retardation protein (FMRP), which is required for normal neural development. Depending on the length of the CGG repeat, the FMR1 gene may be classified as normal (unaffected by the syndrome), a premutation (at risk of Fragile X-associated disorders), or a full mutation (FXS). Males with a full mutation (on their single X chromosome) almost always display symptoms of FXS, while females with a full mutation generally display milder symptoms because of the second X chromosome.


Revolutionizing Genetic Research

While the genetic cause of FXS was beginning to be unraveled, other researchers developed a series of powerful new approaches that would revolutionize genetic research, including the study of FXS. Several scientists, including Gail Martin and her NICHD-supported colleagues, reported the ability to grow and maintain embryonic stem cells that were isolated from mouse embryos. These unique cells came from the center of very early mouse embryos, where they were destined to become all the cell types--from bone to blood to brain--that would form a complete mouse. They would eventually be used to create "designer" mice carrying genetic mutations to mimic human diseases, including FXS. However, additional work was needed before that could be achieved.

Around the same time, another NICHD-supported research group led by Ralph Brinster pioneered methods for transferring genes into cells in order to study how genes worked. Related techniques were developed for creating transgenic mice that carried a randomly inserted gene of interest in every cell of the mouse. One of several ways for creating transgenic mice combined the ability to grow embryonic stem cells in the lab, which Gail Martin had worked out, with gene transfer technology developed by Brinster. It was now possible to insert a gene of interest into mouse embryonic stem cells, inject the genetically altered cells into the eggs of surrogate mouse mothers, and produce transgenic mice carrying the gene of interest in all of their cells. The resulting transgenic mouse could then be studied for the effects of the inserted gene on development as well as effects of the gene in various organs and functions in the adult mouse.

A related area of research moved this technology and the analysis of gene function and genetic disease to a new level. In 2007, Martin Evans, Oliver Smithies, and Mario Capecchi were awarded the Nobel Prize for Physiology or Medicine for the development of what were known as "knockout mice." Dating back to the late 1980s, Smithies and Capecchi were funded by a number of NIH institutes, including NICHD, for the development of a technique known as gene targeting. Existing technologies resulted in genes of interest to be randomly inserted into a cell's DNA. However, in gene targeting, the gene to be inserted into a cell was specially designed to seek out, bind to, and replace the gene that naturally occurred in the cell. This dramatic new advance would allow scientists to replace a normal gene with one that was slightly altered so that it no longer worked, i.e., it was" knocked out." When gene targeting was done in a mouse embryonic stem cell, the altered stem cell could be used to create a "knockout mouse," which was basically "missing" one of its genes. As evidenced by the awarding of the Nobel Prize, this was a groundbreaking technique. Scientists could now determine the exact function of a gene by studying a mouse that lacked the "knocked out" gene.


Knockout Mouse Principles

  • A mutant version of the preselected target gene is constructed in the laboratory.
  • Knockout is achieved by swapping the functional copy of the gene for the mutated version in mouse embryonic stem cells (ES cells).
  • Mice are made using the modified ES cells. These mice carry the same mutation in every cell. An additional round of breeding is required to produce mice that are homozygous for the mutation (there are no copies of the original gene left in the mouse).
  • In traditional knockout mice the mutation is present throughout development and in all cells of the adult. In conditional knockout mice, other genetic strategies are incorporated that allow mutations to be turned on or off at different stages of development or in selected cell types.


Applying Mouse Models to Fragile X in Humans

All of the technologies for creating mouse models of human genetic diseases were now in place. Once the gene that caused a genetic disorder was identified, a version of the gene, that did not function or had limited function, could be used to create a knockout mouse that was an animal model of the human genetic disease. Such animal models could be used to study the progression of a disease, to identify specific physiological and molecular pathways involved in disease development, and to test experimental drugs with the potential to treat the disease. Moreover, an animal model of a disease is extremely valuable for testing the possible benefits as well as the safety of new drugs before proceeding with human clinical trials.

In 1994, the Dutch-Belgian Fragile-X Consortium announced that they had created an Fmr1 knockout mouse that exhibited a number of the hallmarks of human FXS, including learning deficits and hyperactivity, which confirmed that the Fmr1 knockout was a useful mouse model of FXS intellectual disability. Since then, additional Fmr1 knockout animal models were created in fruit flies and zebrafish, and scientists have used animal FXS models to identify brain pathways that appear to be disrupted in animals that lack Fmr1.

These studies revealed that FRMP is needed in a pathway that contributes to brain neurons working properly. The loss of FMRP slows down the activity of neurons and disrupts brain function. The study of FXS animal models resulted in the identification of specific parts of the complex brain networks that do not work properly without FMRP. Many of these parts, usually specific proteins in neurons, are of interest to scientists as "targets" that a new drug could potentially interact with to restore or improve brain activity.

One of these proteins is called the group-1 metabotropic glutamate receptor (mGLuR), which is a protein that is central in the process of neurons sending signals to one another. A drug called MPEP was one of the first compounds tested for its ability to reduce mGLuR in an effort to improve the functioning of the FXS animals. As hoped, MPEP was able to improve some of the behavioral deficits in the animal models, but the drug is not suitable for human clinical trials because of toxic side effects.

However, these initial experiments strongly suggested that testing other drugs that inhibited mGLuR was a worthwhile pursuit. Recent discoveries have revealed a molecular pathway, the mGluR5 signaling cascade External Web Site Policy, that is disrupted in FXS. With this knowledge, further research has provided insights for developing novel medications to normalize the function of this pathway. The mGluR5 signaling cascade may be relevant for extending beyond FXS into a number of other developmental disorders including autism.

Subsequent studies by NICHD researchers and by research groups worldwide continued to make significant progress. New compounds were identified that create the beneficial effects of MPEP without the toxic side effects. The most recent compound identified is AFQ056, which also inhibits mGluR and successfully corrects some of the behavioral abnormalities in the FXS knockout mouse model.


On the Precipice of New Treatments

It might be said that the ultimate goal of the study of genetic disease is to understand it so thoroughly that attempting development of an outright cure becomes the next logical step. Decades of the combined work of studying families with intellectual disability, developing methods of gene transfer, engineering knockout mouse technology, and creating FXS animal models have brought researchers to that point. Now, AFQ056 is being tested in human clinical trials, and other compounds continue to be developed. As genetic technologies enable the understanding of how defective genes result in disease, it is reasonable to expect a shift to the design of treatments that attempt to correct the cause, rather than the symptoms, of genetic disorders.


For More Information

More information on NICHD programs on Intellectual and Developmental Disabilities: Intellectual and Developmental Disabilities Branch

More information on knockout mice: Knockout Mice Fact Sheet

Scientific article: Dölen, G., Osterweil, E., Rao, B.S., Smith, G.B., Auerbach, B.D., Chattarji, S., & Bear, M.F. (2007). Correction of fragile X syndrome in mice. Neuron, 56(6), 955–962.


Last Reviewed: 02/05/2013
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